The present invention relates to metalloproteinase inhibitors and, more particularly, relates to novel compounds, compositions and methods for prophylaxis and treatment of inflammation, tissue degradation and the like. This invention, in particular, relates to novel carboxylic acid substituted heterocyclic compounds, compositions containing such compounds and methods of use of such compounds. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Metalloproteinase enzymes, such as collagenases, stromelysins and gelatinases, may contribute to the onset or etiology of, or exacerbate disease states which are related to, connective tissue degradation and the like. For example, matrix metalloproteinases, such as collagenases, stromelysins and gelatinases, are thought to be involved in the tissue breakdown observed in rheumatoid arthritis; osteoarthritis; osteopenias (e.g., osteoporosis); periodontitis; gingivitis; corneal, epidermal and gastric ulceration; and tumour metastasis, invasion and growth; in neuroinflammatory disorders, such as myelin degradation (e.g., multiple sclerosis); and in angiogenesis dependent diseases, such as arthritic conditions; cancer; solid tumor growth; psoriasis; proliferative retinopathies; neovascular glaucoma; ocular tumours; angiofibromas; hemangiomas; nephritis; pulmonary inflammation; and restenosis.
WO 96/33172 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted 6 membered ring heterocycle hydroxamic acid derivatives, such as N-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds, and their preparation and use as inhibitors of matrix metalloproteinases and TNF production.
EP 606046 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted 5-6 membered ring heterocycle hydroxamic acid derivatives, such as N-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds and N-arylsulfonyl- and N-heteroarylsulfonyl-1,2,3,4-tetrahydroisoquinolinyl-2-hydroxamic acid compounds, preparation and use as inhibitors of matrix metalloproteinases.
WO 97/18194 discloses certain cyclic and heterocyclic N-substituted xcex1-substituted iminohydroxamic a and carboxylic acids, and their preparation and use as inhibitors of matrix metalloproteinases.
EP 803505 discloses optionally substituted aryl fused N-heterocycles and their preparation and use as inhibitors of metalloproteinases.
The present invention relates to selected metalloproteinase inhibitory compounds, analogs and pharmaceutically acceptable salts and prodrugs thereof. The subject compounds are characterized as carboxylic acid substituted heterocyclic compounds. The compounds are useful in the prophylaxis and treatment of inflammation, tissue degradation and related diseases. Therefore, this invention also encompasses pharmaceutical compositions and methods for prophylaxis and treatment of inflamation, tissue degradation and related diseases. The subject invention also relates to processes for making such compounds, as well as to intermediates useful in such processes.
In accordance with the present invention, there is provided a compound of the Formula I below: 
or a pharmacutically acceptable salt thereof, wherein
m is 1 or 2; and n is 0, 1 or 2;
R1 is (1) an alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, amino, alkanoylamino, alkylsulfonylamino, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl or haloalkyl;
preferably, R1 is (1) an C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or ((2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, amino, C1-C8 alkanoylamino, C1-C8 alkylsulfonylamino, C1-C8 alkoxycarbonylamino, C1-C8 alkoxycarbonyl, cyano, halo, azido, C1-C8 alkyl or C1-C8 haloalkyl of 1-3 halo radicals;
more preferably, R1 is (1) a C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, azido, C1-C6 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, R1 is (1) a C1-C12 alkyl radical optionally substituted by 1-3 radicals of xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)R3, xe2x80x94NR3R4, amino, acetylamino, methylsulfonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, C1-C6 alkyl or xe2x80x94CF3 radicals; more preferably, R1 is (1) an C1-C12 alkyl radical optionally substituted by 1-3 radicals of xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)2R , xe2x80x94NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)2R3, xe2x80x94NR3R4, amino, acetylamino, methylsulfonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, C1-C6 alkyl or xe2x80x94CF3 radicals;
more preferably, R1 is (1) an C1-C4 alkyl radical substituted by 1-2 radicals of xe2x80x94OH, xe2x80x94OR3, xe2x80x94NR3R4, aryl or heteroaryl; or (2) an aryl radical optionally substituted by a monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by a phenyl radical; wherein the phenyl, aryl and heteroaryl radicals of (1), (2) and (3) are optionally substituted by 1-2 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)2R3, xe2x80x94NR3R4, amino, acetylamino, methylsulfonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, halo, C1-C6 alkyl or xe2x80x94CF3 radicals;
more preferably, R is aryl or heteroaryl radicals optionally substituted by 1-2 radicals of hydroxy, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)2R3, xe2x80x94NR3R4, amino, acetylamino, methylsulfonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, halo, C1-C6 alkyl or xe2x80x94CF3 radicals; and
more preferably, R1 is an aryl radical optionally substituted by 1-2 radicals of hydroxy, xe2x80x94OR3, xe2x80x94S(O)2R3, xe2x80x94NR3R4, amino, acetylamino, methylsulfonylamino, halo, C1-C4 alkyl or xe2x80x94CF3 radicals;
more preferably, R1 is a phenyl or biphenyl radical optionally substituted by 1-2 radicals of hydroxy, xe2x80x94OR3, xe2x80x94S(O)2R3, xe2x80x94NR3R4, amino, acetylamino, methylsulfonylamino, halo, C1-C4 alkyl or xe2x80x94CF3 radicals;
most preferably, R1 is a phenyl or biphenyl radical optionally substituted by 1-2 radicals of hydroxy, xe2x80x94OR3, halo, methyl or xe2x80x94CF3 radicals; and
provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is preferably 0-3, more preferably, 0-2, most preferably, 1-2;
wherein each R3 is independently an alkyl, haloalkyl, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R3 is independently a C1-C8 alkyl, C1-C8 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C8 alkanoylamino, C1-C8 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C8 alkoxycarbonylamino, C1-C8 alkoxycarbonyl, cyano, halo, azido, C1-C8 alkyl, C1-C8 haloalkyl of 1-3 halo radicals or C1-C8 haloalkoxy of 1-3 halo radicals;
more preferably, each R3 is independently a C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R3 is independently an C1-C4 alkyl, xe2x80x94CF3, aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, acetylamino, methylsulfonylamino, C1-C4 alkylsulfonyl, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3;
more preferably, each R3 is independently a C1-C4 alkyl, xe2x80x94CF3, aryl, heteroaryl, aryl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, acetylamino, methylsulfonylamino, C1-C4 alkylsulfonyl, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3;
more preferably, each R3 is independently a C1-C4 alkyl, xe2x80x94CF3, aryl, heteroaryl, aryl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthiol, amino, acetylamino, methylsulfonylamino, C1-C2 alkylsulfonyl, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, halo, C1-C2 alkyl, xe2x80x94CF3 or xe2x80x94OCF3;
more preferably, each R3 is independently a C1-C4 alkyl, xe2x80x94CF3, aryl, heteroaryl, arylmethyl or heteroarylmethyl radical;
more preferably, each R3 is independently an C1-C4 alkyl, xe2x80x94CF3, phenyl, heteroaryl, phenylmethyl or heteroarylmethyl radical;
most preferably, each R3 is independently an methyl, xe2x80x94CF3, phenyl, heteroaryl, phenylmethyl or heteroarylmethyl radical; and
each R4 is independently a hydrogen or alkyl radical; preferably, each R4 is independently a hydrogen or C1-C8 alkyl radical; more preferably, each R4 is independently a hydrogen or C1-C4 alkyl radical; most preferably, each R4 is independently a hydrogen or methyl radical; and
R11 is a xe2x80x94C(O)xe2x80x94R31, xe2x80x94C(O)xe2x80x94OR30, xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94S(O)2xe2x80x94NR32R31 radical; preferably, R11 is a xe2x80x94C(O)xe2x80x94R31 or xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94S(O)2xe2x80x94NR32R31 radical;
wherein R5 and R6 are each independently a hydrogen or alkyl radical; preferably, R5 and R6 are each independently a hydrogen or C1-C4 alkyl radical; and more preferably, R5 and R6 are each a hydrogen radical; or CR5xe2x80x94CR6 is Cxe2x95x90C (double bonded carbon atoms);
wherein R9 and R10 are each independently -B-A, provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R9, R10 and R11 is 0-3, preferably, 0-2;
wherein each B is independently a (1) bond; (2) alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo, and/or (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy; (3) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy;
preferably, each B is independently a (1) bond; (2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano or halo, and/or (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkyl sulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (3) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoyl-amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl-amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, C1-C8 haloalkyl of 1-3 halo radicals or C1-C8 haloalkoxy of 1-3 halo radicals;
more preferably, each B is independently a (1) bond; (2) C1-C8 alkyl radical optionally substituted by (a) a radical of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, and/or (b) 1-3 halo radicals, and/or (c) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 halo alkoxy of 1-3 halo radicals; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each B is independently a (1) bond; (2) C1-C8 alkyl radical optionally substituted by (a) a radical of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl thio, cyano, and/or (b) 1-3 halo radicals, and/or (c) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkyl sulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals;
more preferably, each B is independently a (1) bond; (2) C1-C4 alkyl radical optionally substituted by (a) a radical of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)-amino, C1-C2 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, and/or (b) 1-2 halo radicals, and/or (c) a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-2 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C2 alkylsulfonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C2 alkylsulfonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals;
more preferably, each B is independently a (1) bond or C1-C4 alkyl radical; or (2) aryl or heteroaryl radical optionally substituted by a radical of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C2 alkylsulfonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; and most preferably, each B is independently a bond, C1-C4 alkyl, aryl, or heteroaryl radical;
wherein each A is independently a (1) hydrogen radical; (2) halo, cyano or nitro radical; (3) xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR31, xe2x80x94C(O)xe2x80x94NR32R31 or xe2x80x94C(NR32)xe2x80x94NR32R31 radical; (4) xe2x80x94OR31, xe2x80x94Oxe2x80x94C(O)xe2x80x94R31, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR32R31 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 radical; (5) xe2x80x94SR31, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR32R31 xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30 or xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR32R31 radical; or (6) xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(NR32)xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94NR32R31 radical;
preferably each A is independently a (1) hydrogen radical; (2) halo, cyano or nitro radical; (3) xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR31, xe2x80x94C(O)xe2x80x94NR32R31 or xe2x80x94C(NR32)xe2x80x94NR32R31 radical; (4) xe2x80x94OR31, xe2x80x94Oxe2x80x94C(O)xe2x80x94R31, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR32R31 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 radical; (5) xe2x80x94SR31, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR32R31, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31, xe2x80x94S(O)2NR33xe2x80x94C(O)xe2x80x94OR30 or xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR32R31 radical; or (6) xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(NR32)xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94NR32R31 radical;
more preferably, each A is independently a hydrogen, halo, cyano, nitro, xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR31, xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94C(NR32)xe2x80x94NR32R31, xe2x80x94OR31, xe2x80x94Oxe2x80x94C(O)xe2x80x94R31, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94SR31, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR32R31, xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(NR32)xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94NR32R31 radical;
more preferably, each A is independently a hydrogen, halo, xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR31, xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94C(NR32)xe2x80x94NR32R31, xe2x80x94OR31, xe2x80x94SR31, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR32R31, xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR32R31, xe2x80x94NR32xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94NR32R31 radical;
more preferably, each A is independently a hydrogen, halo, xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94NR32R3xe2x80x94C(NR32)xe2x80x94NR32R31, xe2x80x94OR31, xe2x80x94SR31, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR32R31, xe2x80x94NR32R31, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R31 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 radical; and most preferably, each A is independently a hydrogen, halo, xe2x80x94C(O)xe2x80x94R30 or xe2x80x94C(O)xe2x80x94NR32R31 radical;
wherein each R30 is independently (1) alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R34, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, arylalkylthio, arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R30 is independently (1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R , amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, Nxe2x80x94((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R30 is independently (1) C1-C6 alkyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R34, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-Nxe2x80x94(C1-C4 alkyl)amino, aminocarbonyl-amino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkyl-sulfonyl, cyano, halo, aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl-amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl-amino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R30 is independently (1) C1-C6 alkyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R34, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, Nxe2x80x94((C1-C4 alkoxy)carbonyl)-Nxe2x80x94(C1-C4 alkyl)amino, aminocarbonyl-amino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkyl-sulfonyl, cyano, halo, aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl-amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl-amino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C2 haloalkyl of 1-3 halo radicals or xe2x80x94OCF3; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals;
more preferably, each R30 is independently (1) xe2x80x94CF3 or C1-C4 alkyl radical optionally substituted by 1-2 radicals of xe2x80x94CO2R34, amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, (C1-C4 alkoxy)-carbonylamino, Nxe2x80x94((C1-C4 alkoxy)carbonyl)xe2x80x94Nxe2x80x94(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy, or aryl-C1-C2-alkoxy, heterocyclyl, aryl or heteroaryl radicals, wherein the heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl) amino, C1-C2 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of (C1-C4 alkoxy)carbonyl, hydroxy or C1-C4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals;
more preferably, each R3 is independently (1) heterocyclyl radical optionally substituted by 1-2 radicals of (C1-C4 alkoxy)carbonyl, hydroxy or C1-C4 alkyl; or (2) heteroaryl radicals optionally substituted by 1-2 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; and
most preferably, each R3 is independently a heterocyclyl radical optionally substituted by C1-C4 alkyl;
wherein each R31 is independently hydrogen radical or (1) alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of -CO2R34, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N-(alkoxycarbonyl)xe2x80x94Nxe2x80x94(alkyl)amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, arylalkylthio, arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl-amino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R31 is independently hydrogen radical or (1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R34, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl-amino, (C1-C4 alkoxy)carbonylamino, Nxe2x80x94((C1-C4 alkoxy) carbonyl)-Nxe2x80x94(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R31 is independently hydrogen radical or (1) C1-C6 alkyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R , amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, Nxe2x80x94((C1-C4 alkoxy)carbonyl)xe2x80x94Nxe2x80x94(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R31 is independently hydrogen radical or (1) C1-C6 alkyl radical optionally substituted by 1-3 radicals of xe2x80x94CO2R34, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, Nxe2x80x94((C1-C4 alkoxy)carbonyl)-Nxe2x80x94(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C2 haloalkyl of 1-3 halo radicals or xe2x80x94OCF3; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals;
more preferably, R31 is independently hydrogen radical or (1) xe2x80x94CF3 or C1-C4 alkyl radical optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy or aryl-C1-C2-alkoxy, aryl or heteroaryl radicals, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl) amino, C1-C2 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; or (2) aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, C1-C2 alkylamino, di-(C1-C2 alkyl)amino, C1-C2 alkanoylamino, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl, xe2x80x94CF3 or xe2x80x94OCF3 radicals; and
most preferably, each R31 is independently hydrogen radical or (1) xe2x80x94CF3 or C1-C4 alkyl radical optionally substituted by 1-2 radicals of aryl or heteroaryl radicals; or (2) aryl or heteroaryl radical;
wherein each R32 is independently (1) hydrogen radical; (2) alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo; or (3) aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy;
preferably, each R32 is independently (1) hydrogen radical; (2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano or halo; or (3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-C8 cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R32 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R32 is independently a hydrogen or methyl radical;
wherein each R33 is independently (1) hydrogen radical; (2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl which is optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; or (3) heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoyl-amino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy;
preferably, each R33 is independently (1) hydrogen radical; (2) C1-C4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl which is optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R33 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R33 is independently a hydrogen or methyl radical; and
wherein each R34 is independently hydrogen, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy;
preferably, each R34 is independently hydrogen or C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R34 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R34 is independently a hydrogen or methyl radical.
The symbols used above have the following meanings: 
For example: 
An aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members means an aryl radical which is optionally substituted by (a) a monocyclic heteroaryl radical of 5-6 ring members optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (b) a monocyclic heterocyclyl radical of 5-6 ring members optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members.
A heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members means a heteroaryl radical which is optionally substituted by (a) a phenyl radical optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; (b) a monocyclic heteroaryl radical of 5-6 ring members optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (c) a monocyclic heterocyclyl radical of 5-6 ring members optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members.
The compounds of this invention have in general several asymmetric centers and are depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers. Preferably, the absolute configuration of the carboxylic acid group is (R). Preferably, the relative configuration of the carboxylic acid group and xe2x80x94NR11R33 is cis, i.e., the carboxylic acid and xe2x80x94NR11R33 are on the same face of the ring system.
Compounds of interest include the following:
3-amino-1-(4-methoxyphenylsulfonyl)azepane-2-carboxylic acid
3-(phenylmethylsulfonylamino)-1-(4-methoxyphenylsulfonyl)azepane-2-carboxylic acid
3-((2-aminophenyl)methylsulfonylamino)-1-(4-methoxyphenylsulfonyl)azepane-2-carboxylic acid
cis-1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethane sulfonylamino)-heptamethyleneimine-2-carboxylic acid
trans-1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethane sulfonylamino)-heptamethyleneimine-2-carboxylic acid
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-1H-azepane-2-carboxylic acid
3-amino-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(methylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(phenylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(naphth-2-ylsulfonylamino)-1-(4-methoxyphenyl sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(naphth-1-ylsulfonylamino)-1-(4-methoxyphenyl sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(phenylmethylsulfonylamino)-1-(4-methoxyphenyl sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-((2-nitrophenyl)methylsulfonylamino)-1-(4-methoxy phenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-((2-phenylethenyl)sulfonylamino)-1-(4-methoxyphenyl sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-((4-iodophenyl)sulfonylamino)-1-(4-methoxyphenyl sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(4-(4-chlorophenyl)phenyl)sulfonylamino)-1-(4-methoxy phenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-(phenylmethoxycarbonylamino)-1-(4-methoxyphenyl sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-((4-trifluoromethylphenyl)methoxycarbonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-((4-chlorophenyl)methoxycarbonylamino)-1-(4-methoxy phenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
3-((3,5-dichlorophenyl)methoxycarbonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
1-(4-Methoxy-benzenesulfonyl)-3-(4-Chlorophenyl-phenylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
1-(4-Methoxy-benzenesulfonyl)-3-(4-chlorophenyl-methanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid
1-(4-Methoxy-benzenesulfonyl)-3(R)-(phenylmethane sulfonylamino)-heptamethyleneimine-2(S)-carboxylic acid
trans-1-(4-Methoxy-benzenesulfonyl)-3(R)-(phenylmethane sulfonylamino)-heptamethyleneimine-2(R)-carboxylic acid.
As utilized herein, the following terms shall have the following meanings:
xe2x80x9cAlkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1-15 carbon atoms (C1-Cl5), more preferably 1-8 carbon atoms (C1-C8), even more preferably 1-6 carbon atoms (C1-C6), yet more preferably 1-4 carbon atoms (C1-C4), still more preferably 1-3 carbon atoms (C1-C3), and most preferably 1-2 carbon atoms (C1-C2). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
xe2x80x9cAlkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), yet more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
xe2x80x9cAlkynylxe2x80x9d, alone or in combination, means a straight-chain or branched chain hydrocarbon radical having one or more triple bonds, preferably 1-2 triple bonds and more preferably one triple bond, and containing preferably 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), yet more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkynyl radicals include ethynyl, propynyl (propargyl), butynyl and the like.
xe2x80x9cAlkoxyxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cOxe2x80x9d is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an alkoxy radical as defined above and xe2x80x9cC(O)xe2x80x9d is a carbonyl radical.
xe2x80x9cAlkoxycarbonylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x9d is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAlkylthioxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Sxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cSxe2x80x9d is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)xe2x80x9d is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)2xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)2xe2x80x9d is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
xe2x80x9cAlkylsulfonylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)2xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94S(O)2xe2x80x94xe2x80x9d is an alkylsulfonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cArylxe2x80x9d, alone or in combination, means a phenyl, biphenyl or naphthyl radical which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and the like. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4xe2x80x94CF3-phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl, 2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4-(4-methoxyphenyl)phenyl, 1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and the like.
xe2x80x9cAryl-alkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 2-naphthylmethyl, 4-methoxyphenylmethyl and the like.
xe2x80x9cAryl-alkoxyxe2x80x9d, alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy and the like.
xe2x80x9cAryloxyxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an aryl radical as defined above.
xe2x80x9cAroylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an aryl radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl.
xe2x80x9cAlkanoylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical. Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
xe2x80x9cAlkanoylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAminocarbonylaminoxe2x80x9d, alone or in combination, means an amino substituted carbonyl substituted on a second amino (ureido) radical, wherein each amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
xe2x80x9cBenzoxe2x80x9d, alone or in combination, means the divalent radical C6H4=derived from benzene.
xe2x80x9cBicyclicxe2x80x9d as used herein is intended to include both fused ring systems, such as naphthyl and xcex2-carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl, naphthyl and diphenylpiperazinyl.
xe2x80x9cCycloalkylxe2x80x9d, alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic alkyl radical, preferably monocyclic, containing preferably 3-10 carbon atoms (C3-C10), more preferably 3-8 carbon atoms (C3-C8), even more preferably 3-6 carbon atoms (C3-C6), which is optionally be benzo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, hydroxycyclopentylpropyl, tetrahydronaphthylpropyl, cyclohexylbutyl and the like.
xe2x80x9cHeteroatomsxe2x80x9d means nitrogen, oxygen and sulfur heteroatoms.
xe2x80x9cHeterocyclylxe2x80x9d, alone or in combination, means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. xe2x80x9cHeterocyclylxe2x80x9d is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems. xe2x80x9cHeterocyclylxe2x80x9d radicals may optionally be substituted on at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. More preferably, xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolnyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heterocyclyl radical as defined above, such as pyrrolidinylmethyl, tetrahydrothienylmethyl, piperidinylethyl and the like.
xe2x80x9cHeteroarylxe2x80x9d, alone or in combination, means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally benzo fused or saturated carbocyclic fused, preferably 3-4 carbon atoms (C3-C4) to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl and heterocyclyl. More preferably, xe2x80x9cheteroarylxe2x80x9d, alone or in combination, is a radical of a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C3-c4-carbocyclic-fused. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 2-(1-piperidinyl)pyridyl, 2-(4-benzyl piperazin-1-yl)-1-pyridinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 1-oxido-2-quinolinyl, isoquinolinyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, 9-carbolinyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.
xe2x80x9cHeteroaroylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an heteroaryl radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl.
xe2x80x9cHeteroaryl-alkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
xe2x80x9cHalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d, alone or in combination, means fluoro, chloro, bromo or iodo radicals.
xe2x80x9cHaloalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
xe2x80x9cHaloalkoxyxe2x80x9d, alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkoxy radicals include 2,2,2-trifluoroethoxy, chloromethoxy, 2-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, bis(trifluoromethyl)methoxy and the like.
xe2x80x9cSulfinylxe2x80x9d, alone or in combination, means a diradical of the type xe2x80x9cxe2x80x94S(O)xe2x80x94xe2x80x9d wherein xe2x80x9cS(O)xe2x80x9d is a mono-oxygenated sulfur atom. xe2x80x9cSulfonylxe2x80x9d, alone or in combination, means a diradical of the type xe2x80x9cxe2x80x94S(O)2xe2x80x94xe2x80x9d wherein xe2x80x9cS(O)2xe2x80x9d is a di-oxygenated sulfur atom.
xe2x80x9cLeaving groupxe2x80x9d generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
xe2x80x9cProtecting groupxe2x80x9d generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
Procedures for preparing the compounds of this invention are set forth below. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
Preparation of Compounds of Formula I
The compounds of the present invention represented by Formula I above can be prepared using various synthesis techniques, many of which are included by reference. In particular, compounds of the present invention can be prepared following the general procedures discussed below.
A general synthesis useful for the preparation of the novel compounds of this invention is illustrated in Scheme I, which employs a convergent route to the azepine ring and larger ring systems. According to this method, the readily available Horner-Emmons reagent is reacted under standard conditions (see Wadsworth, Org. Reactions, 1977, 25, 73) with an aldehyde variably substituted by a silyl ether as well as additional substitution on the alkyl chain (R5, R6, R9, R10) to provide the xcex1,xcex2 unsaturated ester. Deprotection of the silyl group, activation of the alcohol to provide a leaving group and intramolecular base catalyzed closure provides a key intermediate. Subsequent deprotection of the t-BOC group with dry HCl/Ethyl acetate (Gibson, J. Org. Chem., 1994, 59, 3216) or with TFA and 
sulfonylation with a sulfonyl halide in the presence of a base, preferably a hindered amine base such as triethyl amine in a chlorinated solvent provides the substituted sulfonamide. The R group is a group that can be converted into an amino group using methods well known to those skilled in the art, such as benzyl amine, silyl protected benzyl amine, phthalimide, or other readily available nucleophilic amine equivalents. The protected primary amine is deprotected to the unsubstituted primary amine by methods known in the art for example hydrogenation in the presence of a metal catalyst. The primary amine is then funtionalized to provide the ester derivatives of the final product. Methods for funtionalization include sulfonylation as described above, treatment with isocyanates to prepare ureas, treatment with acid chlorides or mixed anhydrides to provide amides, reductive aminations to provide amines, and chloroformates to provide carbamates (See Compendium of Synthetic Organic Methods, Wiley). These adducts are treated with aqueous alkali bases such as LiOH to provide the free acid products when methyl or ethyl esters are used or TFA when the t-butyl ester is used as the ester component.
A second general synthesis useful for the preparation of the novel compounds of this invention is illustrated in Scheme II, which employs a convergent route to the azepine ring.
The readily available aspartic, or glutamic acid derivative is protected and allylated as described previously for an analog (see Baldwin, Tetrahedron, 1989, 45, 6309 and references cited therein). Mitsunobu reaction of the resulting sulfonamide (see Mitsunobu, Synthesis, 1981, 1) provides the bis olefin. Treatment of the resulting olefin with a metathesis reagent (see Schuster, Angew. Chem. Int. Ed. Engl. 1997, 36, 2036) provides the cyclized olefin. Saponification, as known by one skilled in the art, followed by curtius rearangment of the resultant acid under known conditions (Tetrahedron, 1974, 30, 2151) provides the desired carbamates. The t-butyl acid protected carbamates can be deprotected with concentrated trifluoroacetic acid (TFA) to provide the final products. Additionally, by choosing the appropriate alcohol trapping agent for the Curtius rearangement, for example, 4-methoxy benzyl alcohol, the carbamate may be diferentially deprotected to the amine with dilute (3%) TFA in a chlorinated solvent to provide the t-butyl protected acid, amine salt. Sulfonylation, as described previously, or treatment with the appropriate alkylating or acylating agent as known by one skilled in the art and deprotection of the t-butyl ester as described provides the compounds. Larger rings can be formed by using homologues of allyl-iodide or hydroxy-allyl, such as 4-iodo-1-butene, 4-hydroxy-1-butene, 5-iodo-1-pentene, 5-hydroxy-1-pentene, 4-iodo-2-butene, 4-hydroxy-2-butene and the like. 
Intermediates from Scheme II can be used as starting materials for substituents R5, R6, R9 and R10. For example, the aspartic acid derivative can be alkylated with a variety of polysubstiuted allyl iodides or triflates such as CH2xe2x95x90CH2CHR7R10I followed by Mitzunubu reaction with with allyl and homoallyl alcohols to provide intermediates for methathesis reaction. The compounds claimed may also be prepared by funtionalization of the olefinic intermediates after metathesis. For example, the olefin can be hydrogenated under standard conditions, preferably, Pd/C under an atmosphere of hydrogen in a solvent such as a alcohol,or ethyl acetate. The olefin can be hydroborated with a borane reagent,(see Brown, Borane Reagents, Academic Press, NY, 1988) preferably, BH3xe2x80x94DMS, and the subsequent borane complex oxidized with H2O2 to provide the alcohol or with cromium agents under standard conditions (see Hudlicky, Oxidations in Organic Chemistry, ACS mongraph 186, 1990), provides the ketone. The ketone can serve as a electrophil with wittig reagents, organometallic agents or can be reacted with aldehydes under basic or acidic conditions to undergo aldol condensations. The olefins can undergo allylic oxidation with chromium or preferably selenium reagents (see Rabjohn, Org. Reactions, 1976, 24, 261) as known in the art to provide allylic alcohols which activated as a leaving group and can be substituted with carbon, oxygen, nitrogen or sulphur nucleophiles as known in the art under neutral or basic conditions with or without palladium or lewis acid catalysis. Additional compounds can be prepared by treatment of the olefin with a aryl or alkenyl halide or triflate in the presence of a palladium catalyst to undergo a Heck reaction.(for an extensive review of bond formation using palladium catalysis see Tsuji, Palladium Reagents and Catalysis, Wiley, 1995) The formed olefin can be funtionalized as described above to provide additional substitution. The olefin can be epoxidized with MCPBA or a related peroxide to for the epoxide that can be substituted in the presence or absence or a lewis acid with a reactive Carbon, nitrogen, oxygen or sulphur nucleophil as known in the art.
Alternatively, substituted urea derivatives can be prepared by reacting the isocyanate intermediate formed in the Curtius rearrangement by using an amine (HNR31R32) in place of the alcohol (R30xe2x80x94OH) (Scheme III). 
Further, the carbamate formed in Scheme II can be hydrolyzed in acid to the free amine (Scheme IV) which can then be derivatized, such as by alkylation, reductive alkylation, sulfonylation, aminosulfonylation, acylated and the like, such as in Scheme V. 
It is apparent from the above description that no single general synthesis can be used in the preparation of all of the novel compounds of this invention, because some of the radicals, well known to those skilled in the art, will or may have the potential of interfering with, competing with or inhibiting the some of the reactions involved in the pathway. However, one skilled in the art is fully aware of appropriate point in the synthetic pathway when a radical may be introduced and when protecting groups can be used.
Sulfonyl halides can be prepared by the reaction of a suitable alkyl, aryl, heteroaryl, heterocyclyl and the like Grignard or lithium reagents with sulfuryl chloride, or sulfur dioxide followed by oxidation with a halogen, preferably chlorine. Alkyl, heteroaryl, heterocyclyl, aryl and the like Grignard or lithium reagents can be prepared from their corresponding halide (such as chloro or bromo) compounds which are commercially available or readily prepared from commercially available starting materials using known methods in the art. Alternatively, mercaptans may be oxidized to sulfonyl chlorides using chlorine in the presence of water under carefully controlled conditions. Additionally, sulfonic acids may be converted into sulfonyl halides using reagents such as PCl5, SOCl2, ClC(O)C(O)Cl and the like, and also to anhydrides using suitable dehydrating reagents. The sulfonic acids are either commercially available or may be prepared using procedures well known in the art from commercially available starting materials. In place of the sulfonyl halides, sulfinyl halides or sulfenyl halides can be utilized to prepare compounds wherein the sulfonyl moiety is replaced by an sulfinyl or thio moiety, respectively. Arylsulfonic acids, benzo fused heterocyclyl sulfonic acids or heteroaryl sulfonic acids can be prepared by sulfonation of the aromatic ring by well known methods in the art, such as by reaction with sulfuric acid, SO3, SO3 complexes, such as DMF(SO3), pyridine(SO3), N,N-dimethylacetamide(SO3), and the like. Preferably, such sulfonyl halides are prepared from such aromatic compounds by reaction with DMF(SO3) and SOCl2 or ClC(O)C(O)Cl. The reactions may be performed stepwise or in a single pot.
Additional R1 substitution can be obtained by further reactions on the sulfonamide after reaction of the sulfonyl halide with the related amine. For instance, nitro substituted aryl or heteroaryl sulphonamides can be reduced to the aniline and substituted or converted to the diazonium salt and reacted further to provide the described compounds by methods known to one skilled in the art. Additional R1 substitutions can be obtained by reaction of fluorine, halogen, or trifluoromethanesulfonyloxy substituted aryl or heteroaryl or alkyl sulfonyl chlorides with the related amine followed by substitution of the reactive intermediate with oxygen, nitrogen, sulfur or carbon nucleophile in the presence or absence of a transition metal catalyst such as palladium to provide the desired compounds.(For a monograph on the topic, see Miller, Aromatic Nucleophilic Substitution, Elsevier, N.Y., 1968).
Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids, heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans, heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides, heterocyclylhalides, heteroarylhalides, and the like are commercially available or can be readily prepared from starting materials commercially available using standard methods well known in the art.
Thioether derivatives can be converted into the corresponding sulfone or sulfoxide by oxidizing the thioether derivative with a suitable oxidation agent in a suitable solvent. Suitable oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, oxone (potassium peroxy monosulfate), meta-chloroperoxy benzoic acid, periodic acid and the like, including mixtures thereof. Suitable solvents include acetic acid (for sodium meta-perborate) and, for other peracids, ethers such as THF and dioxane, and acetonitrile, DMF and the like, including mixtures thereof.
The compounds of the invention may be produced in racemic or optically pure form. When a single enantiomer is prepared, these may be synthesized by beginning with optically pure starting materials, by resolution of a basic or acidic racemic intermediate with the appropriate chiral acid or base respectivily, as known to one skilled in the art, or by the addition of a chiral protecting group to the racemic intermediate or final product where the diasteriomeric pair can be seperated by chromatoraphy or crystallization.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily prepared from known starting materials.
Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
All reagents were used as received without purification. All proton and carbon NMR spectra were obtained on a Bruker nuclear magnetic resonance spectrometer.
The following Examples illustrate the preparation of compounds of the present invention and intermediates useful in preparing the compounds of the present invention.